Electroconvulsive stimulation elicits antidepressant-like effects via βCaMKII-dependent lateral habenula modulation

BACKGROUND: Electroconvulsive therapy (ECT) remains a highly effective intervention for acute episodes of major depressive disorder, offering rapid and robust antidepressant effects. However, its underlying mechanisms remain unclear, as prior studies focusing on conventional brain regions (e.g., the hippocampus) have not fully accounted for ECT's distinct therapeutic profile compared to slow-acting antidepressants. Emerging evidence implicates the lateral habenula (LHb) in mediating rapid antidepressant responses. Nevertheless, its role in ECT's efficacy and the involvement of key molecular targets within the LHb remain unexplored. METHODS: We investigated the impact of electroconvulsive stimulation (ECS, an animal model of ECT) on depressive-like behaviors and neurological alterations in the LHb, hippocampus, and prefrontal cortex (PFC). Using a chronic restraint stress (CRS) mouse model of depression, we administered ECS and assessed behavioral outcomes alongside molecular and synaptic changes in different brain regions. To assess mechanistic involvement, we modulated βCaMKII expression in the LHb. RESULTS: ECS ameliorated CRS-induced depressive-like behaviors and reversed synaptic abnormalities in the LHb and hippocampus. ECS induced region-specific bidirectional changes in protein expression profiles in the LHb versus hippocampus, corresponding to its opposing effects on CRS-induced depressive impairments in these brain regions. Notably, LHb βCaMKII overexpression abolished all therapeutic effects of ECS. CONCLUSION: These findings identify the LHb as a crucial target for ECS-induced antidepressant-like effects, mediated through region-specific mechanisms that require βCaMKII-dependent synaptic modulation within the LHb.